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MGP000506

UniProt Annotations

Entry Information
Gene Namecyclin-dependent kinase 4
Protein EntryCDK4_HUMAN
UniProt IDP11802
SpeciesHuman
Comments
Comment typeDescription
Alternative ProductsEvent=Alternative splicing; Named isoforms=2; Name=1; IsoId=P11802-1; Sequence=Displayed; Name=2; IsoId=P11802-2; Sequence=VSP_056487; Note=No experimental confirmation available.;
Catalytic ActivityATP + a protein = ADP + a phosphoprotein. {ECO:0000269|PubMed:19075005, ECO:0000269|PubMed:19237565, ECO:0000269|PubMed:9106657}.
DiseaseMelanoma, cutaneous malignant 3 (CMM3) [MIM:609048]: A malignant neoplasm of melanocytes, arising de novo or from a pre- existing benign nevus, which occurs most often in the skin but also may involve other sites. {ECO:0000269|PubMed:7652577, ECO:0000269|PubMed:8528263, ECO:0000269|PubMed:9311594, ECO:0000269|PubMed:9425228}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
Enzyme RegulationBoth phosphorylation at Thr-172 and binding of a D-type cyclin are necessary for enzymatic activity. Full activation of the cyclin-D-CDK4 complex appears to require other factors such as recruitment of the substrate via a substrate recruitment motif, and/or formation of the CDKN1B ternary complex. Inhibited by INK4 family members. In resting cells, the non- tyrosine-phosphorylated form of CDKN1B prevents phosphorylation at Thr-172 and inactivation, while, in proliferating cells, tyrosine phosphorylation of CDKN1B allows phosphorylation of Thr-172 of CDK4 and subsequennt activation. {ECO:0000269|PubMed:19487459}.
FunctionSer/Thr-kinase component of cyclin D-CDK4 (DC) complexes that phosphorylate and inhibit members of the retinoblastoma (RB) protein family including RB1 and regulate the cell-cycle during G(1)/S transition. Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complexes and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase. Hypophosphorylates RB1 in early G(1) phase. Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals. Also phosphorylates SMAD3 in a cell-cycle-dependent manner and represses its transcriptional activity. Component of the ternary complex, cyclin D/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex. {ECO:0000269|PubMed:15241418, ECO:0000269|PubMed:18827403, ECO:0000269|PubMed:9003781}.
InteractionP24385:CCND1; NbExp=11; IntAct=EBI-295644, EBI-375001; P30281:CCND3; NbExp=8; IntAct=EBI-295644, EBI-375013; Q16543:CDC37; NbExp=7; IntAct=EBI-295644, EBI-295634; P38936:CDKN1A; NbExp=5; IntAct=EBI-295644, EBI-375077; P46527:CDKN1B; NbExp=5; IntAct=EBI-295644, EBI-519280; P42771:CDKN2A; NbExp=9; IntAct=EBI-295644, EBI-375053; P42772:CDKN2B; NbExp=8; IntAct=EBI-295644, EBI-711280; P42773:CDKN2C; NbExp=3; IntAct=EBI-295644, EBI-711290; P08238:HSP90AB1; NbExp=3; IntAct=EBI-295644, EBI-352572; P01106:MYC; NbExp=2; IntAct=EBI-295644, EBI-447544; P28749:RBL1; NbExp=2; IntAct=EBI-295644, EBI-971402; Q8N720:ZNF655; NbExp=3; IntAct=EBI-295644, EBI-625509;
PtmPhosphorylation at Thr-172 is required for enzymatic activity. Phosphorylated, in vitro, at this site by CCNH-CDK7, but, in vivo, appears to be phosphorylated by a proline-directed kinase. In the cyclin D-CDK4-CDKN1B complex, this phosphorylation and consequent CDK4 enzyme activity, is dependent on the tyrosine phosphorylation state of CDKN1B. Thus, in proliferating cells, CDK4 within the complex is phosphorylated on Thr-172 in the T- loop. In resting cells, phosphorylation on Thr-172 is prevented by the non-tyrosine-phosphorylated form of CDKN1B. {ECO:0000269|PubMed:16782892, ECO:0000269|PubMed:19075005, ECO:0000269|PubMed:19237555, ECO:0000269|PubMed:19237565, ECO:0000269|PubMed:19369195, ECO:0000269|PubMed:19487459}.
SimilarityBelongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. {ECO:0000305}.
SimilarityContains 1 protein kinase domain. {ECO:0000255|PROSITE-ProRule:PRU00159}.
Subcellular LocationCytoplasm. Nucleus. Membrane. Note=Cytoplasmic when non-complexed. Forms a cyclin D-CDK4 complex in the cytoplasm as cells progress through G(1) phase. The complex accumulates on the nuclear membrane and enters the nucleus on transition from G(1) to S phase. Also present in nucleoli and heterochromatin lumps. Colocalizes with RB1 after release into the nucleus.
SubunitComponent of the D-CDK4 complex, composed of CDK4 and some D-type G1 cyclin (CCND1, CCND2 or CCND3). Interacts directly in the complex with CCND1, CCND2 or CCND3. Interacts with SEI1 and ZNF655. Forms a ternary complex, cyclin D-CDK4-CDKN1B, involved in modulating CDK4 enzymatic activity. Interacts directly with CDKN1B (phosphorylated on 'Tyr-88' and 'Tyr-89'); the interaction allows assembly of the cyclin D-CDK4 complex, Thr-172 phosphorylation, nuclear translocation and enhances the cyclin D-CDK4 complex activity. CDK4 activity is either inhibited or enhanced depending on stoichiometry of complex. The non-tyrosine-phosphorylated form of CDKN1B prevents T-loop phosphorylation of CDK4 producing inactive CDK4. Interacts (unphosphorylated form) with CDK2. Also forms ternary complexes with CDKN1A or CDKN2A. Interacts directly with CDKN1A (via its N-terminal); the interaction promotes the assembly of the cyclin D-CDK4 complex, its nuclear translocation and promotes the cyclin D-dependent enzyme activity of CDK4. Interacts with CCND1; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression. {ECO:0000269|PubMed:10580009, ECO:0000269|PubMed:15558030, ECO:0000269|PubMed:16782892, ECO:0000269|PubMed:18827403, ECO:0000269|PubMed:19075005, ECO:0000269|PubMed:19124461, ECO:0000269|PubMed:19237555, ECO:0000269|PubMed:19237565, ECO:0000269|PubMed:9106657}.
Web ResourceName=Atlas of Genetics and Cytogenetics in Oncology and Haematology; URL="http://atlasgeneticsoncology.org/Genes/CDK4ID238ch12q14.html";
Web ResourceName=NIEHS-SNPs; URL="http://egp.gs.washington.edu/data/cdk4/";
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